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Gastrointestinal Stromal Tumors Treatment (PDQ®)

General Information About Gastrointestinal Stromal Tumors (GIST)

Epidemiology

Although they comprise fewer than 1% of all gastrointestinal (GI) tumors, GIST are the most common mesenchymal tumors of the GI tract.[1] It has been estimated that there are 3,300 to 6,000 new GIST cases per year in the United States.[2] A study based on Surveillance, Epidemiology and End Results (SEER) registry data found that the age-adjusted yearly incidence of GIST in the United States was 6.8 per million from 1992 to 2000.[3] However, the true incidence is not known, in part because many tumors have not been tested for the characteristic KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene mutations. In addition, small, indolent GIST, only a few millimeters in diameter, are common in the general population and are not included in cancer registries.[4,5] GIST are equally distributed across all geographic and ethnic groups and men and women are equally affected. Most patients present between the ages of 50 and 80.[6] The vast majority of GIST are sporadic, but there are rare familial forms associated with the characteristic heritable mutations in the KIT gene (or, rarely, in succinate dehydrogenase genes in Carney-Stratakis syndrome). Familial GIST may present as multiple primary tumors.

Clinical Presentation and Diagnostic Evaluation

GIST can occur anywhere along the GI tract, but most often are found in the stomach or small intestine. The American Joint Committee on Cancer (AJCC) Cancer Staging Manual lists the following approximate distributions:[7]

Stomach (60%).

Small intestine (30%).

Rectum (3%).

Colon (1–2%).

Esophagus (<1%).

Omentum/mesentery (rare).

Gastrointestinal stromal tumors (GISTs) may be found anywhere in or near the gastrointestinal tract.

Less frequently, GIST may arise in the appendix, gallbladder, pancreas, retroperitoneum, and paravaginal and periprostatic tissues.[8] Approximately 20% to 25% of gastric GIST and 40% to 50% of small intestinal GIST are clinically aggressive.[9,10] It has been estimated that approximately 10% to 25% of patients present with metastatic disease.[9,11]

The clinical presentation of patients with GIST varies depending on the anatomic location of the tumor and the tumor size and aggressiveness.[12] The most common presentation of GIST is GI bleeding, which may be acute (melena or hematemesis) or chronic and results in anemia.[10]

Smaller lesions may be incidental findings during surgery, radiologic studies, or endoscopy. The natural history of these incidental tumors and the frequency of progression to symptomatic disease are unknown. There may be a substantial reservoir of small GIST tumors that do not progress to symptomatic stages. For example, a series of 98 consecutive systematic autopsies on adults who died of unrelated causes revealed grossly recognizable gastric tumors (1 mm–6 mm) that were histologically diagnosed as GIST in 22.5% of cases.[5] Sufficient DNA was available for analysis in 26 patients, revealing 13 patients with mutations in KIT exon 11 and one in PDGFRA.

In a retrospective study of 200 GIST cases, typical clinical manifestations of malignancy included liver metastases and/or dissemination within the abdominal cavity. Lymph node involvement and spread to the lungs or other extra-abdominal sites was unusual.[11] Advanced disease may be associated with metastases to distant sites, including lung and bone. Brain metastases are rare.[2]

GIST should be included in the differential diagnosis of any intra-abdominal nonepithelial malignancy. Diagnostic interventions may include the following:[12]

Computed tomography (CT).

Magnetic resonance imaging.

Upper GI endoscopy.

Tests that may be useful in staging include the following:

18FDG-PET (18fluoro-deoxyglucose-positron emission tomography).

CT.

Endoscopic ultrasound with fine-needle aspiration biopsy is useful in the detection of GIST in the upper GI tract because most tumors arise below the mucosal layer and grow in an endophytic fashion.[12-14]

Because nodal metastasis is so rare at diagnosis (i.e., it is virtually unheard of for true GIST according to the AJCC Cancer Staging Manual [7]), there is general agreement that nodal dissection is not needed.

Pathology and Molecular Genetics

Typically arising within the muscle wall of the GI tract, GIST range in size from less than 1 cm to more than 40 cm, with an average size of approximately 5 cm when diagnosed clinically.[2] Small GIST may form solid subserosal, intramural, or, less frequently, polypoid intraluminal masses. Large tumors tend to form external masses attached to the outer aspect of the gut involving the muscular layers.[2] GIST morphology is quite varied; the tumors are composed of the following:[8]

Spindle cells (70%).

Epithelioid cells (20%).

Mixed spindle and epithelioid cells (10%).

GIST encompass a broad continuum of histologic patterns, ranging from bland-appearing tumors with very low mitotic activity (often previously designated leiomyomas) to very aggressive-appearing patterns (previously often called leiomyosarcomas).[7] They may originate from interstitial cells of Cajal (ICC) or their stem cell-like precursors, although this is not certain.[15,16]

The most commonly used marker for GIST is the CD117 antigen, a marker expressed by ICC. Approximately 95% of GISTs are positive for the CD117 antigen, an epitope of the KIT receptor tyrosine kinase.[2,9] However, CD117 immunohistochemistry is not specific for GIST, as weak reactivity occurs with other mesenchymal neoplasms; accordingly, morphologic examination and the use of other immunostains in difficult cases are indispensible.[17] In addition, false-positive CD117 staining can occur if antigen retrieval techniques are used in the pathology laboratory to enhance marker expression.[18] Because of a relatively broad morphologic spectrum, the differential diagnosis of GIST includes several mesenchymal, neural, and neuroendocrine neoplasms that occur in the abdomen including the following:[8]

Leiomyoma.

Leiomyosarcoma.

Schwannoma.

Malignant peripheral-nerve sheath tumor.

Solitary fibrous tumor.

Inflammatory myofibroblastic tumor.

Fibromatosis.

Synovial sarcoma.

Neuroendocrine tumors (carcinoid and islet cell).

Gastric glomus tumor.

Malignant mesothelioma.

Angiosarcoma.

Sarcomatoid carcinoma.

Approximately 85% of GIST contain oncogenic mutations in one of two receptor tyrosine kinases: KIT or PDGFRA (platelet-derived growth factor receptor alpha).[2,10] Constitutive activation of either of these receptor tyrosine kinases plays a central role in the pathogenesis of GIST.[15,19] Wild-type tumors, with no detectable KIT or PDGFRA mutations, account for 12% to 15% of all GIST. Fewer than 5% of GIST occur in the setting of syndromic diseases, such as neurofibromatosis type 1 (NF1), Carney triad syndrome, and other familial diseases.[2,20-22] The correct identification of GIST is very important because of the availability of specific, molecular-targeted therapy with KIT/PDGFRA tyrosine kinase inhibitors (TKI) such as imatinib mesylate or, in the case of imatinib-resistant GIST, sunitinib malate.[1,10,17]

Risk Assessment and Prognosis

At the time of clinical presentation, the prognosis appears to be influenced by genetic events other than kinase mutations, although a particular kinase mutation may help to define the initial clinical course of a GIST. Based on retrospective studies from time periods that predated the clinical use of kinase inhibitors, current recommendations for assessing the risk of progression for a newly diagnosed primary GIST rely on three parameters (see Table 1):[2,23-26]

Survival

Compared to other intra-abdominal sarcomas, survival in GIST patients after surgery alone is favorable.[27] In a retrospective study involving 200 patients that predated the use of TKI, the 5-year disease-specific survival rate for GIST patients with primary disease who underwent complete resection of gross disease (N = 80) was 54%, with survival predicted by tumor size; the overall disease-specific survival was 35% at 5 years.[11] Other studies, which also predated TKI, reported 5-year survival rates of 40% to 63% for patients undergoing complete resections of GIST.

In the retrospective study of 200 patients cited in Table 1 above, 7% had isolated local recurrence and 47% had metastasis.[11] The site of relapse for GIST is usually intra-abdominal, involving the peritoneum, the liver, or both; true local recurrences are uncommon, and typically there is widespread intraperitoneal recurrence that may not be detectable by imaging techniques.[27] The median disease-specific survival of patients with metastatic GIST (N = 94) was 19 months.[11] In one retrospective study involving 119 patients with metastatic GIST, it was found that once a GIST becomes metastatic, kinase genotype did not factor into overall survival.[28]

The median time to recurrence for patients on imatinib is 2 years.[27]

Follow-up

The most appropriate tests and frequency of testing for metastatic or recurrent disease in patients who have undergone GIST resection are ill-defined, since the impact of follow-up strategies on clinical outcomes is not known. Follow-up recommendations are, therefore, based upon expert opinion and clinical judgment taking into account tumor site, size, and mitotic index. For surgically treated patients with localized disease, routine follow-up schedules may differ across institutions and may depend on the risk status of the tumor.[18] Abdominal/pelvic CT may be performed every 3 to 6 months, but very low-risk lesions may not need routine follow-up testing.[18]

CT or 18FDG-PET are used to monitor therapeutic effects in patients receiving systemic therapy for unresectable, metastatic, or recurrent disease.[27] 18FDG-PET may also be helpful in detecting resistance to TKI. If 18FDG-PET is used to monitor therapy with a TKI, a baseline FDG-PET is often performed before kinase inhibitor administration. Because 18FDG-PET imaging may detect the activity of imatinib in GIST much earlier than CT imaging, imaging of GIST with 18FDG-PET may represent a useful diagnostic modality for the very early assessment of response to imatinib therapy; a decrease in tumor avidity for 18FDG may be detected as early as 24 hours after a single dose of imatinib.[12]